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1.  Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac 
Cell Cycle  2016;15(3):381-393.
Previous studies have indicated that inflammatory stimulation represses protein phosphatase 2A (PP2A), a well-known tumor suppressor. However, whether PP2A repression participates in pancreatic cancer progression has not been verified. We used lipopolysaccharide (LPS) and macrophage-conditioned medium (MCM) to establish in vitro inflammation models, and investigated whether inflammatory stimuli affect pancreatic cancer cell growth and invasion PP2A catalytic subunit (PP2Ac)-dependently. Via nude mouse models of orthotopic tumor xenografts and dibutyltin dichloride (DBTC)-induced chronic pancreatitis, we evaluated the effect of an inflammatory microenvironment on PP2Ac expression in vivo. We cloned the PP2Acα and PP2Acβ isoform promoters to investigate the PP2Ac transcriptional regulation mechanisms. MCM accelerated pancreatic cancer cell growth; MCM and LPS promoted cell invasion. DBTC promoted xenograft growth and metastasis, induced tumor-associated macrophage infiltration, promoted angiogenesis, activated the nuclear factor-κB (NF-κB) pathway, and repressed PP2Ac expression. In vitro, LPS and MCM downregulated PP2Ac mRNA and protein. PP2Acα overexpression attenuated JNK, ERK, PKC, and IKK phosphorylation, and impaired LPS/MCM-stimulated cell invasion and MCM-promoted cell growth. LPS and MCM activated the NF-κB pathway in vitro. LPS and MCM induced IKK and IκB phosphorylation, leading to p65/RelA nuclear translocation and transcriptional activation. Overexpression of the dominant negative forms of IKKα attenuated LPS and MCM downregulation of PP2Ac, suggesting inflammatory stimuli repress PP2Ac expression NF-κB pathway–dependently. Luciferase reporter gene assay verified that LPS and MCM downregulated PP2Ac transcription through an NF-κB–dependent pathway. Our study presents a new mechanism in inflammation-driven cancer progression through NF-κB pathway–dependent PP2Ac repression.
PMCID: PMC4943687  PMID: 26761431
inflammation; LPS; NF-κB; PP2A; pancreatic cancer; TAM
2.  Prognostic significance of Ki67 in Chinese women diagnosed with ER+/HER2− breast cancers by the 2015 St. Gallen consensus classification 
BMC Cancer  2017;17:28.
This study evaluated the distribution pattern of the Ki67-labeling index (LI) among patients at a Chinese breast cancer center, and analyzed its prognostic significance in the 2015 St Gallen consensus breast cancer classification, estrogen receptor-positive and human epidermal growth factor receptor 2-negative(ER+/HER2−)subtype.
We classified 939 women with ER+/HER2− breast cancer into three groups by Ki67-LI levels, and followed their clinicopathologic characteristics and prognoses.
In the 939 eligible subjects, 342 had Ki67-LI ≤10% (Ki67Low), 281 had Ki67-LI between 10 and 30% (Ki67Medium), and 316 had Ki67-LI ≥30% (Ki67High). Although the Ki67High group had less favorable clinicopathologic factors, the Ki67Medium group’s factors varied considerably. Kaplan-Meier estimates showed that disease-free survival(DFS) for the Ki67Medium group was significantly shorter than the Ki67Low group but longer than the Ki67High group. Ki67-LI had independent prognostic significance in multivariate analysis. Other diagnostic factors, including tumor size >2 cm, positive lymph nodes, and grade III disease, were significantly associated with poorer disease-free survival only in the Ki67Medium group.
For patients with ER+/HER2− breast cancer, we confirmed three distinct risk patterns by Ki67-LI levels according to the 2015 St Gallen consensus. For patients with clearly low or high Ki67-LI, straightforward clinical decisions could be offered, but for patients with intermediate Ki67-LI, other factors might provide valuable information.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-3021-7) contains supplementary material, which is available to authorized users.
PMCID: PMC5219721  PMID: 28061893
ER+/HER2− breast cancer; Ki67-labeling index; Prognosis
3.  Recommendations for Updating T and N Staging Systems for Nasopharyngeal Carcinoma in the Era of Intensity-Modulated Radiotherapy 
PLoS ONE  2016;11(12):e0168470.
The aim of this study was to compare the 2008 Chinese and the 7th edition of the American Joint Committee on Cancer (AJCC) staging systems for nasopharyngeal carcinoma and to provide proposals for updating T and N staging systems of the present staging system.
Between January 2007 and December 2012, a cohort of 752 patients with biopsy-proven, newly diagnosed, non-metastatic nasopharyngeal carcinoma who were treated with intensity-modulated radiotherapy were retrospectively analysed. Prognoses were compared by T stage, N stage, and clinical stage according to the two staging systems for overall survival (OS), local relapse-free survival (LRFS), and distant metastasis-free survival (DMFS).
In terms of both the T and N staging systems, the two current staging systems were comparable in predicting OS. The T classification of the 2008 Chinese staging system was better in predicting LRFS, while the N classification of the 7th edition AJCC staging system was superior in predicting DMFS. In the modern era of intensity-modulated radiotherapy, the staging system should be updated by down-staging the current stage T2 to T1, and it might be rational to merge subcategories N1 and N2.
The two current staging systems each had advantages in predicting prognosis. It seems reasonable to downstage T2 to T1 and to merge N1 and N2.
PMCID: PMC5156424  PMID: 27973544
4.  Tuning the role of charge-transfer states in intramolecular singlet exciton fission through side-group engineering 
Nature Communications  2016;7:13622.
Understanding the mechanism of singlet exciton fission, in which a singlet exciton separates into a pair of triplet excitons, is crucial to the development of new chromophores for efficient fission-sensitized solar cells. The challenge of controlling molecular packing and energy levels in the solid state precludes clear determination of the singlet fission pathway. Here, we circumvent this difficulty by utilizing covalent dimers of pentacene with two types of side groups. We report rapid and efficient intramolecular singlet fission in both molecules, in one case via a virtual charge-transfer state and in the other via a distinct charge-transfer intermediate. The singlet fission pathway is governed by the energy gap between singlet and charge-transfer states, which change dynamically with molecular geometry but are primarily set by the side group. These results clearly establish the role of charge-transfer states in singlet fission and highlight the importance of solubilizing groups to optimize excited-state photophysics.
The understanding of how a singlet exciton separates into triplet states in organic semiconductors is crucial to the design of efficient organic solar cells. Here, Lukman et al. identify the role played by charge-transfer states during triplet formation through side-group engineering of pentacenes.
PMCID: PMC5150654  PMID: 27924819
5.  Endothelial NADPH oxidase 4 protects ApoE−/− mice from atherosclerotic lesions 
Vascular reactive oxygen species (ROS) are known to be involved in atherosclerosis development and progression. NADPH oxidase 4 (Nox4) is a constitutively active ROS-producing enzyme that is highly expressed in the vascular endothelium. Nox4 is unique in its biology and has been implicated in vascular repair, however, the role of Nox4 in atherosclerosis is unknown. Therefore, to determine the effect of endothelial Nox4 on development of atherosclerosis, Apoe E−/− mice +/− endothelial Nox4 (ApoE−/−+EC Nox4) were fed a high cholesterol/high fat (Western) diet for 24 weeks. Significantly fewer atherosclerotic lesions were observed in the ApoE−/− + EC Nox4 mice as compared to the ApoE−/− littermates, which was most striking in the abdominal region of the aorta. In addition, markers of T cell populations were markedly different between the groups; T regulatory cell marker (FoxP3) was increased whereas T effector cell marker (T-bet) was decreased in aorta from ApoE−/− + EC Nox4 mice compared to ApoE−/− alone. We also observed decreased monokine induced by gamma interferon (MIG; CXCL9), a cytokine known to recruit and activate T cells, in plasma and tissue from ApoE−/− + EC Nox4 mice. To further investigate the link between endothelial Nox4 and MIG expression, we utilized cultured endothelial cells from our EC Nox4 transgenic mice and human cells with adenoviral overexpression of Nox4. In these cultured cells, upregulation of Nox4 attenuated endothelial cell MIG expression in response to interferon-gamma. Together these data suggest that endothelial Nox4 expression reduces MIG production and promotes a T cell distribution that favors repair over inflammation, leading to protection from atherosclerosis.
PMCID: PMC4783146  PMID: 26169727
NADPH Oxidase 4; reactive oxygen species; atherosclerosis; T regulatory cells; CXCL9
6.  Urbanization Level and Vulnerability to Heat-Related Mortality in Jiangsu Province, China 
Environmental Health Perspectives  2016;124(12):1863-1869.
Although adverse effects of high temperature on mortality have been studied extensively in urban areas, little is known of the heat–mortality associations outside of cities.
We investigated whether heat–mortality associations differed between urban and nonurban areas and how urbanicity affected the vulnerability to heat-related mortality.
We first analyzed heat-related mortality risk in each of 102 counties in Jiangsu Province, China, during 2009–2013 using a distributed-lag nonlinear model. The county-specific estimates were then pooled for more urban (percentage of urban population ≥ 57.11%) and less urban (percentage of urban population < 57.11%) counties using a Bayesian hierarchical model. To explain the spatial variation in associations by county, county-level characteristics affecting heat vulnerability were also examined.
We found that the overall mortality risk comparing the 99th vs. 75th percentiles of temperature was 1.43 [95% posterior intervals (PI): 1.36, 1.50] in less urban counties and 1.26 (95% PI: 1.23, 1.30) in more urban counties. The heat effects on cardiorespiratory mortality followed a similar pattern. Higher education level and prevalence of air conditioning were significantly associated with counties having lower risks, whereas percentage of elderly people was significantly associated with increased risks.
Our findings reveal that nonurban areas have significant heat-related mortality risks in Jiangsu, China. These results suggest the need for enhanced adaptation planning in Chinese nonurban areas under a changing climate.
Chen K, Zhou L, Chen X, Ma Z, Liu Y, Huang L, Bi J, Kinney PL. 2016. Urbanization level and vulnerability to heat-related mortality in Jiangsu Province, China. Environ Health Perspect 124:1863–1869;
PMCID: PMC5132638  PMID: 27152420
7.  Calmodulin interacts with Rab3D and modulates osteoclastic bone resorption 
Scientific Reports  2016;6:37963.
Calmodulin is a highly versatile protein that regulates intracellular calcium homeostasis and is involved in a variety of cellular functions including cardiac excitability, synaptic plasticity and signaling transduction. During osteoclastic bone resorption, calmodulin has been reported to concentrate at the ruffled border membrane of osteoclasts where it is thought to modulate bone resorption activity in response to calcium. Here we report an interaction between calmodulin and Rab3D, a small exocytic GTPase and established regulator osteoclastic bone resorption. Using yeast two-hybrid screening together with a series of protein-protein interaction studies, we show that calmodulin interacts with Rab3D in a calcium dependent manner. Consistently, expression of a calcium insensitive form of calmodulin (i.e. CaM1234) perturbs calmodulin-Rab3D interaction as monitored by bioluminescence resonance energy transfer (BRET) assays. In osteoclasts, calmodulin and Rab3D are constitutively co-expressed during RANKL-induced osteoclast differentiation, co-occupy plasma membrane fractions by differential gradient sedimentation assay and colocalise in the ruffled border as revealed by confocal microscopy. Further, functional blockade of calmodulin-Rab3D interaction by calmidazolium chloride coincides with an attenuation of osteoclastic bone resorption. Our data imply that calmodulin- Rab3D interaction is required for efficient bone resorption by osteoclasts in vitro.
PMCID: PMC5126571  PMID: 27897225
8.  Glucose-Dependent Insulinotropic Polypeptide Ameliorates Mild Traumatic Brain Injury-Induced Cognitive and Sensorimotor Deficits and Neuroinflammation in Rats 
Journal of Neurotrauma  2016;33(22):2044-2054.
Mild traumatic brain injury (mTBI) is a major public health issue, representing 75–90% of all cases of TBI. In clinical settings, mTBI, which is defined as a Glascow Coma Scale (GCS) score of 13–15, can lead to various physical, cognitive, emotional, and psychological-related symptoms. To date, there are no pharmaceutical-based therapies to manage the development of the pathological deficits associated with mTBI. In this study, the neurotrophic and neuroprotective properties of glucose-dependent insulinotropic polypeptide (GIP), an incretin similar to glucagon-like peptide-1 (GLP-1), was investigated after its steady-state subcutaneous administration, focusing on behavior after mTBI in an in vivo animal model. The mTBI rat model was generated by a mild controlled cortical impact (mCCI) and used to evaluate the therapeutic potential of GIP. We used the Morris water maze and novel object recognition tests, which are tasks for spatial and recognition memory, respectively, to identify the putative therapeutic effects of GIP on cognitive function. Further, beam walking and the adhesive removal tests were used to evaluate locomotor activity and somatosensory functions in rats with and without GIP administration after mCCI lesion. Lastly, we used immunohistochemical (IHC) staining and Western blot analyses to evaluate the inflammatory markers, glial fibrillary acidic protein (GFAP), amyloid-β precursor protein (APP), and bone marrow tyrosine kinase gene in chromosome X (BMX) in animals with mTBI. GIP was well tolerated and ameliorated mTBI-induced memory impairments, poor balance, and sensorimotor deficits after initiation in the post-injury period. In addition, GIP mitigated mTBI-induced neuroinflammatory changes on GFAP, APP, and BMX protein levels. These findings suggest GIP has significant benefits in managing mTBI-related symptoms and represents a novel strategy for mTBI treatment.
PMCID: PMC5116684  PMID: 26972789
amyloid-β precursor protein; BMX; cognitive dysfunction; controlled cortical impact; GFAP; glucagon-like peptide-1; glucose-dependent insulinotropic polypeptide; mild traumatic brain injury; neuroinflammation
9.  Effects of increased positive end-expiratory pressure on intracranial pressure in acute respiratory distress syndrome: a protocol of a prospective physiological study 
BMJ Open  2016;6(11):e012477.
There are concerns that the use of positive end-expiratory pressure (PEEP) in patients with brain injury may potentially elevate intracranial pressure (ICP). However, the transmission of PEEP into the thoracic cavity depends on the properties of the lungs and the chest wall. When chest wall elastance is high, PEEP can significantly increase pleural pressure. In the present study, we investigate the different effects of PEEP on the pleural pressure and ICP in different respiratory mechanics.
Methods and analysis
This study is a prospective, single-centre, physiological study in patients with severe brain injury. Patients with acute respiratory distress syndrome with ventricular drainage will be enrolled. An oesophageal balloon catheter will be inserted to measure oesophageal pressure. Patients will be sedated and paralysed; airway pressure and oesophageal pressure will be measured during end-inspiratory occlusion and end-expiratory occlusion. Elastance of the chest wall, the lungs and the respiratory system will be calculated at PEEP levels of 5, 10 and 15 cm H2O. We will classify each patient based on the maximal ΔICP/ΔPEEP being above or below the median for the study population. 2 groups will thus be compared.
Ethics and dissemination
The study protocol and consent forms were approved by the Institutional Review Board of Fujian Provincial Hospital. Study findings will be disseminated through peer-reviewed publications and conference presentations.
Trial registration number
NCT02670733; pre-results.
PMCID: PMC5128838  PMID: 27852713
Oesophageal pressure; Acute respiratory distress syndrome; Positive end-expiration pressure; Intracranial pressure
10.  miR-589-5p inhibits MAP3K8 and suppresses CD90+ cancer stem cells in hepatocellular carcinoma 
Cancer stem cells (CSCs) are important in the tumorigenesis and progression of hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) play crucial roles regulating CD133+ and EpCAM+ CSCs in HCC, although it is unclear whether miRNAs regulate CD90+ CSCs in HCC.
The miRNA profiles of CD90+ and CD90- HCC cells were analyzed using a miRNA microarray and quantitative real-time PCR (qRT-PCR). CSC characteristics were examined by qRT-PCR and Western blot of pluripotency-associated genes, clone and sphere formation assay, transwell migration assay, and nude mice tumorigenicity assay. miR-589-5p mimic transfection was used to overexpress miR-589-5p in vitro. The CD90 and miR-589-5p expressions of HCC samples were detected by immunohistochemistry and qRT-PCR, respectively.
miR-589-5p and miR-33b-5p were down-regulated in CD90+ cells. Overexpression of miR-589-5p suppressed CD90+ CSC characteristics such as Oct4, Sox2 and Nanog expression, a high likelihood of forming cell spheres, high invasiveness and high tumorigenicity. Luciferase reporter assays demonstrated that miR-589-5p directly binds to the 3ˈ-untranslated region of mitogen-activated protein kinase kinase kinase 8 (MAP3K8) mRNA, and exogenous miR-589-5p down-regulated MAP3K8 expression. In addition, siRNA inhibition of MAP3K8 also suppressed CD90+ CSC characteristics, even in the absence of miR-589-5p overexpression. In HCC tissues, miR-589-5p expression was inversely correlated with CD90 expression, and high CD90 expression and low miR-589-5p expression were positively correlated with vascular invasion and recurrence and significantly decreased disease-free and overall survival by clinical analysis.
In HCC, miR-589-5p down-regulates the stemness characteristics of CD90+ CSCs in part by silencing MAP3K8. CD90 and miR-589-5p expression predict HCC outcomes and might be novel molecular targets for HCC treatment.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-016-0452-6) contains supplementary material, which is available to authorized users.
PMCID: PMC5106831  PMID: 27835990
Cellular heterogeneity; Tumorigenicity; CD90; microRNA; MAP3K8; Prognosis
11.  Portulacerebroside A inhibits adhesion, migration, and invasion of human leukemia HL60 cells and U937 cells through the regulation of p38/JNK signaling pathway 
OncoTargets and therapy  2016;9:6953-6963.
Acute myeloid leukemia (AML) is a highly malignant hematopoietic tumor. This study aimed to explore the effect of portulacerebroside A (PCA) on the adhesion, migration, and invasion in human leukemia HL60 cells and U937 cells and clarify the possible mechanisms involved, which could provide potential strategies for the treatment of AML. By methyl thiazolyl tetrazolium analysis, it was found that PCA (1–10 μM) suppressed the cell viability in a time- and dose-dependent manner. A total of 1, 2, and 5 μM of PCA dramatically inhibited the adhesion, migration, and invasion of HL60 cells and U937 cells in a dose-dependent manner. Phosphorylation level of JNK and P38 protein level was measured by Western blot. After the real-time quantification polymerase chain reaction and Western blot detection of the total RNA and protein, messenger RNA, and protein expression levels of Ras homologous C (RhoC), metastasis-associated gene 1 (MTA1) and matrix metalloproteinase-2/9 (MMP-2/9) were decreased significantly in a dose-dependent manner. The phosphorylation level of c-Jun N-terminal kinase (JNK) and P38 mitogen-activated protein kinase (P38) was decreased dramatically in HL60 cells and U937 cells after PCA treatment. In conclusion, PCA significantly inhibits the adhesion, migration, and invasion of HL60 cells and U937 cells by suppressing the p38/JNK pathway and regulating the expressions of related genes.
PMCID: PMC5113926  PMID: 27956839
portulacerebroside A; PCA; p38/JNK; leucocythemia; adhesion; migration; invasion
12.  Why are hospital doctors not referring to Consultation-Liaison Psychiatry? – a systemic review 
BMC Psychiatry  2016;16:390.
Consultation-Liaison Psychiatry (CLP) is a subspecialty of psychiatry that provides care to inpatients under non-psychiatric care. Despite evidence of benefits of CLP for inpatients with psychiatric comorbidities, referral rates from hospital doctors remain low. This review aims to understand barriers to CLP inpatient referral as described in the literature.
We searched on Medline, PsychINFO, CINAHL and SCOPUS, using MESH and the following keywords: 1) Consultation-Liaison Psychiatry, Consultation Liaison Psychiatry, Consultation Psychiatry, Liaison Psychiatry, Hospital Psychiatry, Psychosomatic Medicine, the 2) Referral, Consultation, Consultancy and 3) Inpatient, Hospitalized patient, Hospitalized patient. We considered papers published between 1 Jan 1965 and 30 Sep 2015 and all articles written in English that contribute to understanding of barriers to CLP referral were included.
Thirty-five eligible articles were found and they were grouped thematically into three categories: (1) Systemic factors; (2) Referrer factors; (3) Patient factors. Systemic factors that improves referrals include a dedicated CLP service, active CLP consultant and collaborative screening of patients. Referrer factors that increases referrals include doctors of internal medicine specialty and comfortable with CLP. Patients more likely to be referred tend to be young, has psychiatric history, live in an urban setting or has functional psychosis.
This is the first systematic review that examines factors that influence CLP inpatient referrals. Although there is research in this area, it is of limited quality. Education could be provided to hospital doctors to better recognise mental illness. Collaborative screening of vulnerable groups could prevent inpatients from missing out on psychiatric care. CLP clinicians should use the knowledge gained in this review to provide quality engagement with referrers.
PMCID: PMC5103418  PMID: 27829386
Consultation-Liaison Psychiatry; Hospital psychiatry; Barriers to referral; Consultation inpatient
13.  Rapid and reversible photoinduced switching of a rotaxane crystal 
Nature Communications  2016;7:13321.
Crystalline phase transitions caused by external stimuli have been used to detect physical changes in the solid-state properties. This study presents the mechanical switching of crystals of ferrocene-containing rotaxane controlled by focused laser light. The expansion and contraction of the crystals can be driven by turning on and off laser light at 445 nm. The irradiation-induced expansion of the crystal involves elongation along the a, b and c axes at 30 °C, whereas heating of the crystal at 105 °C causes the shortening of c axis. The expansions reversibly occur and have the advantage of a rapid relaxation (reverse) process. Single-crystal X-ray crystallography reveals the detailed structural changes of the molecules, corresponding to a change in the size of the crystals on laser irradiation. This molecular crystal behaviour induced by laser irradiation, is demonstrated for the remote control of objects, namely, microparticle transport and microswitching in an electric circuit.
Crystalline phase transition can be used to detect changes in the solid state properties of materials. Here, the authors describe the mechanical response of a crystal composed of ferrocene-containing rotaxane to laser irradiation.
PMCID: PMC5097158  PMID: 27808090
14.  Haplodeficiency of Klotho Gene Causes Arterial Stiffening via Upregulation of Scleraxis Expression and Induction of Autophagy 
Hypertension  2015;66(5):1006-1013.
The prevalence of arterial stiffness increases with age while the level of the aging-suppressor protein klotho decreases with age. The objective of this study is to assess if haplodeficiency of klotho gene causes arterial stiffness and investigate the underlying mechanism. Pulse wave velocity, a direct measure of arterial stiffness, was increased significantly in klotho heterozygous (klotho+/−) mice vs. their age-matched wild-type (WT) littermates, suggesting that haplodeficiency of klotho causes arterial stiffening. Notably, plasma aldosterone levels were elevated significantly in klotho+/− mice. Treatment with eplerenone (6 mg/kg/day, IP), an aldosterone receptor blocker, abolished klotho deficiency-induced arterial stiffening in klotho+/− mice. Klotho deficiency was associated with increased collagen and decreased elastin contents in the media of aortas. In addition, arterial MMP2, MMP9 and TGFβ1 expression and myofibroblast differentiation were increased in klotho+/− mice. These klotho deficiency-related changes can be blocked by eplerenone. Protein expression of scleraxis, a transcription factor for collagen synthesis, and LC3-II/LC3-I, an index of autophagy, were upregulated in aortas of klotho+/− mice, which can be abolished by eplerenone. In cultured mouse aortic smooth muscle cells, aldosterone increased collagen-1 expression which can be completely eliminated by siRNA knockdown of scleraxis. Interestingly, alsosterone decreased elastin levels in smooth muscle cells which can be abolished by siRNA knockdown of Beclin-1, an autophagy-related gene.
This study demonstrated for the first time that klotho deficiency-induced arterial stiffening may involve aldosterone-mediated upregulation of scleraxis and induction of autophagy which led to increased collagen-1 expression and decreased elastin levels, respectively.
PMCID: PMC4600046  PMID: 26324504
arterial stiffness; scleraxis; autophagy; Beclin-1; myofibroblast; collagen; elastin; smooth muscle cell
15.  Metformin Use Is Associated With Better Survival of Breast Cancer Patients With Diabetes: A Meta-Analysis 
The Oncologist  2015;20(11):1236-1244.
This meta-analysis showed that metformin was associated with better overall survival times and cancer-specific survival times in diabetic patients with breast cancer. Subgroup analysis revealed that metformin improved the overall survival by 65% after adjusting for hormone receptor expression. The findings of this study highlight the potential usage of metformin in diabetic patients with breast cancer.
Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pathologic complete response rate than do diabetic patients not receiving metformin, but findings on salvage treatment have been inconsistent. We performed a meta-analysis to assess the effect of adding metformin to standard therapy on the prognosis of breast cancer patients with diabetes.
We searched PubMed, Embase, Web of Science (Thomson Scientific), China Knowledge Resource Integrated Database, VIP journal integration platform, and Chinese BioMedical Literature Database from inception to January 10, 2015, without language restrictions, including references related to metformin, breast cancer, and prognosis. We performed the meta-analysis using a random-effects model, with hazard ratios (HRs) and 95% confidence intervals (95% CIs) as effect measures.
A total of 11 studies consisting of 5,464 breast cancer patients with diabetes were included, comprising 2,760 patients who had received metformin and 2,704 patients who had not. The meta-analysis showed that metformin was associated with better overall survival times (HR: 0.53; 95% CI: 0.39-0.71) and cancer-specific survival times (HR: 0.89; 95% CI: 0.79-1.00). Subgroup analysis revealed that metformin improved the overall survival by 65% after adjusting for hormone receptor expression (HR: 0.35; 95% CI: 0.15–0.84). Taking metformin after the diagnosis of breast cancer was still associated with prolonged overall survival.
The use of metformin in standard cancer therapy might improve both overall and cancer-specific survivals of diabetic patients with breast cancer.
Implications for Practice:
Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pathologic complete response rate than diabetic patients not receiving metformin, but findings on salvage treatment have been inconsistent. The meta-analysis showed that metformin was associated with better overall survival times and cancer-specific survival times. Subgroup analysis revealed that metformin improved the overall survival by 65% after adjusting for hormone receptor expression. Taking metformin after the diagnosis of breast cancer was still associated with prolonged overall survival. The findings of this study highlight the potential usage of metformin in diabetic patients with breast cancer.
PMCID: PMC4718443  PMID: 26446233
Metformin; Breast cancer; Diabetes mellitus; Survival; Meta-analysis
16.  Towards an understanding of the propensity for crystalline hydrate formation by molecular compounds 
IUCrJ  2016;3(Pt 6):430-439.
The propensity for crystalline hydrate formation by molecular compounds that are devoid of strong hydrogen-bond donors has been analyzed and rationalized through a Cambridge Structural Database (CSD) survey, systematic hydrate screening experiments and computational studies.
Hydrates are technologically important and ubiquitous yet they remain a poorly understood and understudied class of molecular crystals. In this work, we attempt to rationalize propensity towards hydrate formation through crystallization studies of molecules that lack strong hydrogen-bond donor groups. A Cambridge Structural Database (CSD) survey indicates that the statistical occurrence of hydrates in 124 molecules that contain five- and six-membered N-heterocyclic aromatic moieties is 18.5%. However, hydrate screening experiments on a library of 11 N-heterocyclic aromatic compounds with at least two acceptor moieties and no competing hydrogen-bond donors or acceptors reveals that over 70% of this group form hydrates, suggesting that extrapolation from CSD statistics might, at least in some cases, be deceiving. Slurrying in water and exposure to humidity were found to be the most effective discovery methods. Electrostatic potential maps and/or analysis of the crystal packing in anhydrate structures was used to rationalize why certain molecules did not readily form hydrates.
PMCID: PMC5094445  PMID: 27840682
molecular hydrates; CSD survey; hydrate screening experiments; electrostatic potential; hydrogen bonding; N-heterocyclic aromatic compounds
17.  Abundant DNA 6mA methylation during early embryogenesis of zebrafish and pig 
Nature Communications  2016;7:13052.
DNA N6-methyldeoxyadenosine (6mA) is a well-known prokaryotic DNA modification that has been shown to exist and play epigenetic roles in eukaryotic DNA. Here we report that 6mA accumulates up to ∼0.1–0.2% of total deoxyadenosine during early embryogenesis of vertebrates, but diminishes to the background level with the progression of the embryo development. During this process a large fraction of 6mAs locate in repetitive regions of the genome.
DNA 6mA is a poorly understood epigenetic mark present at a low abundance in eukaryotic genomes. Here the authors observe high levels in zebrafish and pig during early embryogenesis enriched to repetitive regions of the genome and followed by attenuation during development.
PMCID: PMC5059759  PMID: 27713410
18.  Environmental and Ecological Risk Assessment of Trace Metal Contamination in Mangrove Ecosystems: A Case from Zhangjiangkou Mangrove National Nature Reserve, China 
BioMed Research International  2016;2016:2167053.
Zhangjiangkou Mangrove National Nature Reserve is a subtropical wetland ecosystem in southeast coast of China, which is of dense population and rapid development. The concentrations, sources, and pollution assessment of trace metals (Cu, Cd, Pb, Cr, Zn, As, and Hg) in surface sediment from 29 sites and the biota specimen were investigated for better ecological risk assessment and environmental management. The ranges of trace metals in mg/kg sediment were as follows: Cu (10.79–26.66), Cd (0.03–0.19), Pb (36.71–59.86), Cr (9.67–134.51), Zn (119.69–157.84), As (15.65–31.60), and Hg (0.00–0.08). The sequences of the bioaccumulation of studied metals are Zn > Cu > As > Cr > Pb > Cd > Hg with few exceptions. Cluster analysis and principal component analysis revealed that the trace metals in the studied area mainly derived from anthropogenic activities, such as industrial effluents, agricultural waste, and domestic sewage. Pollution load index and geoaccumulation index were calculated for trace metals in surface sediments, which indicated unpolluted status in general except Pb, Cr, and As.
PMCID: PMC5067478  PMID: 27795956
19.  Intraoperative Assessment of Final Margins with a Handheld Optical Imaging Probe During Breast-Conserving Surgery May Reduce the Reoperation Rate: Results of a Multicenter Study 
Annals of surgical oncology  2015;22(10):3356-3362.
A multicenter, prospective, blinded study was performed to test the feasibility of using a handheld optical imaging probe for the intraoperative assessment of final surgical margins during breast-conserving surgery (BCS) and to determine the potential impact on patient outcomes.
Forty-six patients with early-stage breast cancer (one with bilateral disease) undergoing BCS at two study sites, the Johns Hopkins Hospital and Anne Arundel Medical Center, were enrolled in this study. During BCS, cavity-shaved margins were obtained and the final margins were examined ex vivo in the operating room with a probe incorporating optical coherence tomography (OCT) hardware and interferometric synthetic aperture microscopy (ISAM) image processing. Images were interpreted after BCS by three physicians blinded to final pathology-reported margin status. Individual and combined interpretations were assessed. Results were compared to conventional postoperative histopathology.
A total of 2,191 images were collected and interpreted from 229 shave margin specimens. Of the eight patients (17 %) with positive margins (0 mm), which included invasive and in situ diseases, the device identified all positive margins in five (63 %) of them; reoperation could potentially have been avoided in these patients. Among patients with pathologically negative margins (>0 mm), an estimated mean additional tissue volume of 10.7 ml (approximately 1 % of overall breast volume) would have been unnecessarily removed due to false positives.
Intraoperative optical imaging of specimen margins with a handheld probe potentially eliminates the majority of reoperations.
PMCID: PMC4839389  PMID: 26202553
20.  Optimization of a Coastal Environmental Monitoring Network Based on the Kriging Method: A Case Study of Quanzhou Bay, China 
BioMed Research International  2016;2016:7137310.
Environmental monitoring is fundamental in assessing environmental quality and to fulfill protection and management measures with permit conditions. However, coastal environmental monitoring work faces many problems and challenges, including the fact that monitoring information cannot be linked up with evaluation, monitoring data cannot well reflect the current coastal environmental condition, and monitoring activities are limited by cost constraints. For these reasons, protection and management measures cannot be developed and implemented well by policy makers who intend to solve this issue. In this paper, Quanzhou Bay in southeastern China was selected as a case study; and the Kriging method and a geographic information system were employed to evaluate and optimize the existing monitoring network in a semienclosed bay. This study used coastal environmental monitoring data from 15 sites (including COD, DIN, and PO4-P) to adequately analyze the water quality from 2009 to 2012 by applying the Trophic State Index. The monitoring network in Quanzhou Bay was evaluated and optimized, with the number of sites increased from 15 to 24, and the monitoring precision improved by 32.9%. The results demonstrated that the proposed advanced monitoring network optimization was appropriate for environmental monitoring in Quanzhou Bay. It might provide technical support for coastal management and pollutant reduction in similar areas.
PMCID: PMC5061993  PMID: 27777951
21.  Stereoselective alkoxycarbonylation of unactivated C(sp3)–H bonds with alkyl chloroformates via Pd(II)/Pd(IV) catalysis 
Nature Communications  2016;7:12901.
Several examples on Pd-catalysed carbonylation of methyl C(sp3)–H bonds with gaseous CO via Pd(II)/Pd(0) catalysis have been reported. However, methylene C(sp3)–H carbonylation remains a great challenge, largely due to the lack of reactivity of C–H bonds and the difficulty in CO migratory insertion. Herein, we report the stereoselective alkoxycarbonylation of both methyl and methylene C(sp3)–H bonds with alkyl chloroformates through a Pd(II)/Pd(IV) catalytic cycle. A broad range of aliphatic carboxamides and alkyl chloroformates are compatible with this protocol. In addition, this process is scalable and the directing group could be easily removed under mild conditions with complete retention of configuration.
Carbonylation of unactivated C-H bonds is typically carried out on primary C-H sites using gaseous carbon monoxide. Here the authors report a palladium cataylsed alkoxycarbonylation process using alkyl chloroformates that functionalises more challenging unactivated secondary C-H sites.
PMCID: PMC5052708  PMID: 27678161
22.  Betulinic acid exerts anti-hepatitis C virus activity via the suppression of NF-κB- and MAPK-ERK1/2-mediated COX-2 expression 
British Journal of Pharmacology  2015;172(18):4481-4492.
Background and Purpose
This study was designed to evaluate the effect of betulinic acid (BA), extracted from Avicennia marina, on the replication of hepatitis C virus (HCV) and to investigate the mechanism of this BA-mediated anti-HCV activity.
Experimental Approach
HCV replicon and infectious systems were used to evaluate the anti-HCV activity of BA. Exogenous COX-2 or knock-down of COX-2 expression was used to investigate the role of COX-2 in the anti-HCV activity of BA. The effects of BA on the phosphorylation of NF-κB and on kinases in the MAPK signalling pathway were determined. The anti-HCV activity of BA in combination with other HCV inhibitors was also determined to assess its use as an anti-HCV supplement.
Key Results
BA inhibited HCV replication in both Ava5 replicon cells and in a cell culture-derived infectious HCV particle system. Treatment with a combination of BA and IFN-α, the protease inhibitor telaprevir or the NS5B polymerase inhibitor sofosbuvir resulted in the synergistic suppression of HCV RNA replication. Exogenous overexpression of COX-2 gradually attenuated the inhibitory effect of BA on HCV replication, suggesting that BA reduces HCV replication by suppressing the expression of COX-2. In particular, BA down-regulated HCV-induced COX-2 expression by reducing the phosphorylation of NF-κB and ERK1/2 of the MAPK signalling pathway.
Conclusions and Implications
BA inhibits HCV replication by suppressing the NF-κB- and ERK1/2-mediated COX-2 pathway and may serve as a promising compound for drug development or as a potential supplement for use in the treatment of HCV-infected patients.
PMCID: PMC4562509  PMID: 26102077
23.  Rationale and design of the cardiorespiratory fitness and hospitalization events in armed forces study in Eastern Taiwan 
World Journal of Cardiology  2016;8(8):464-471.
To investigate the association between cardiorespiratory fitness and hospitalization events in a cohort of large voluntary arm forces in Taiwan.
The cardiorespiratory fitness and hospitalization events in armed forces (CHIEF) is a retrospective cohort consisting of more than 4000 professional military members aged 18-50 years in Eastern Taiwan. All participants received history taking, physical examination, chest radiography, 12-lead electrocardiography, blood tests for cell counts and fasting glucose, lipid profiles, uric acid, renal function and liver function in the Hualien Armed Forces General Hospital during 2014. In addition, participants were required to undergo two indoor resistant exercise tests including 2-min push-up and 2-min sit-up, both scored by infrared sensing, and one outdoor endurance 3000-m none weight-bearing running test, the main indicator of cardiorespiratory fitness in the Military Physical Training and Testing Center in Eastern Taiwan in 2014.
Hospitalization events for cardiovascular disease, acute kidney injury, rhabdomyolysis, severe infectious disease, acute psychiatric illness, diabetes, orthopedic surgery and mortality will be identified in the National Insurance Research Database for 10 years.
CHIEF will be among the largest Eastern Asian armed forces cohort, in which physical status was strictly evaluated to follow up the hospitalization events for severe illness.
PMCID: PMC4997527  PMID: 27621774
Cardiorespiratory fitness; Hospitalization; Voluntary armed forces
24.  7th drug hypersensitivity meeting: part one 
Carr, Daniel F. | Chung, Wen-Hung | Jenkiins, Rosalind E. | Chaponda, Mas | Nwikue, Gospel | Cornejo Castro, Elena M. | Antoine, Daniel J. | Pirmohamed, Munir | Wuillemin, Natascha | Dina, Dolores | Eriksson, Klara K. | Yerly, Daniel | Pavlos, Rebecca | Mckinnin, Elizabeth | Ostrov, David | Peters, Bjoern | Buus, Soren | Koelle, David | Chopra, Abha | Rive, Craig | Redwood, Alec | Restrepo, Susana | Bracey, Austin | Yuan, Jing | Gaudieri, Silvana | Carrington, Mary | Haas, David | Mallal, Simon | Phillips, Elizabeth | De Boer, Douwe | Menheere, Paul | Nieuwhof, Chris | Bons, Judith | Jonsson, Friederike | De Chaisemartin, Luc | Granger, Vanessa | Gillis, Caitlin | Gouel, Aurelie | Neukirch, Catherine | Dib, Fadia | Nicaise, Pascale Roland | Longrois, Dan | Tubach, Florence | Martin, Sylvie | Bruhns, Pierre | Chen, Kai-Lung | Liao, Shu-Ling | Sheen, Yi-Shuan | Cho, Yung-Tsu | Yang, Che-Wen | Liau, Jau-Yu | Chu, Chia-Yu | Aguiar, Rita | Lopes, Anabela | Fernandes, Natália | Viegas, Leonor | Pereira-Barbosa, M. A. | Bünter, Antonia | Gupta, Nisha | Petkovic, Tatjana Pecaric | Wirth, Nicole | Pichler, Werner J. | Hausmann, Oliver | Yazicioglu, Mehtap | Ozdemir, Pinar G. | Ciplak, Gokce | Kaya, Ozkan | Cooke, Peter John | Mota, Inês | Gaspar, Ângela | Benito-Garcia, Filipe | Chambel, Marta | Morais-Almeida, Mário | Marques, Luis | Alcoceba, Eva | Lara, Silvia | Carneiro-Leão, Leonor | Botelho, Carmen | Dias-Castro, Eunice | Cernadas, Josefina R. | Nicholls, Katherine | Lay, William | Smith, Olivia | Collins, Christine | Unglik, Gary | Spriggs, Kymble | Auyeung, Priscilla | McComish, Jeremy | Douglass, Jo A. | Peter, Jonny G. | Potter, Paul | Carolino, Fabrícia | De Castro, Eunice Dias | Moreira, Ana Sofia | Abreu, Carmo | Gomes, Eva | Cardoso, Bárbara Kong | Tomaz, Elza | Correia, Sara | Inácio, Filipe | Arnold, Annabelle | Bear, Natasha | Rueter, Kristina | Gong, Grace | O’Sullivan, Michael | Muthusamy, Saravanan | Noble, Valerie | Lucas, Michaela | Buterleviciute, Neringa | Rudzeviciene, Odilija | Abreu, Carmo | May, Sara | Pongdee, Thanai | Park, Miguel | Griguola, Linas | Vinikovas, Arturas | Kašinskaite, Simona | Kvedariene, Violeta | Aktas, Ayse | Rahman, Suheyla | Elbi, Huseyin | Ozyurt, Beyhan Cengiz | Cavkaytar, Ozlem | Karaatmaca, Betul | Cetinkaya, Pinar Gur | Esenboga, Saliha | Sahiner, Umit M. | Sekerel, Bulent E. | Soyer, Ozge | Zubrinich, Celia | Tong, Bianca | Patel, Mittal | Giles, Michelle | O’Hehir, Robyn | Puy, Robert | Amaral, Luís | Demir, Semra | Gelincik, Asli | Olgac, Muge | Caskun, Raif | Unal, Derya | Colakoglu, Bahauddin | Buyukozturk, Suna | Matute, Olga Vega | Bernad, Amalia | Gastaminza, Gabriel | Madamba, Roselle | Lacasa, Carlos | Goikoetxea, M. J. | D’Amelio, Carmen | Rifón, Jose | Martínez, Nicolas | Ferrer, Marta | Ribeiro, Carmelita | Faria, Emília | Frutuoso, Cristina | Barros, Anabela | Lebre, Rosário | Pego, Alice | Bom, Ana Todo | Ensina, Luis Felipe | Aranda, Carolina | Nunes, Ines Camelo | Martins, Ana Maria | Solé, Dirceu | Bavbek, Sevim | Kendirlinan, Resat | Çerçi, Pamir | Tutluer, Seda | Soyyigit, Sadan | Sözener, Zeynep Çelebi | Aydin, Ömür | Gümüsburun, Reyhan | Almeida, Marta | Sai, Kimie | Imatoh, Takuya | Nakamura, Ryosuke | Fukazawa, Chisato | Hinomura, Yasushi | Saito, Yoshiro | Sousa-Pinto, Bernardo | Correia, Cláudia | Gomes, Lídia | Gil-Mata, Sara | Araújo, Luís | Delgado, Luís | Sai, Kimie | Okamoto-Uchida, Yoshimi | Kajinami, Koji | Matsunaga, Kayoko | Aihara, Michiko | Wang, Chuang-Wei | Su, Shih-Chi | Hung, Shuen-Iu | Ho, Hsin-Chun | Yang, Chih-Hsun | Paulmann, Maren | Dunant, Ariane | Mockenhaupt, Maja | Sekula, Peggy | Schumacher, Martin | Kardaun, Sylvia | Naldi, Luigi | Bellón, Teresa | Creamer, Daniel | Haddad, Cynthia | Sassolas, Bruno | Lebrun-Vignes, Bénédicte | Valeyrie-Allanore, Laurence | Roujeau, Jean-Claude | Paulmann, Maren | Kremmler, Carmen | Mockenhaupt, Maja | Dodiuk-Gad, Roni P. | Olteanu, Cristina | Feinstein, Anthony | Hashimoto, Rena | Alhusayen, Raed | Whyte-Croasdaile, Sonia | Finkelstein, Yaron | Burnett, Marjorie | Sade, Shachar | Cartotto, Robert | Jeschke, Marc | Shear, Neil H. | Takamura, Naoko | Yamane, Yumiko | Matsukura, Setsuko | Nakamura, Kazuko | Watanabe, Yuko | Yamaguchi, Yukie | Kambara, Takeshi | Ikezawa, Zenro | Aihara, Michiko | Hashimoto, Rena | Chew, Hall | Burnett, Marjorie | Jeschke, Marc | Knezevic, Brittany | Ionmhain, Una Nic | Barraclough, Allison | Anstey, Matthew | Usui, Toru | Meng, Xiaoli | Farrell, John | Whitaker, Paul | Watson, John | French, Neil | Park, Kevin | Naisbitt, Dean | Neves, Ana Castro | Cadinha, Susana | Moreira, Ana | Da Silva, J. P. Moreira | Drvar, Daniela Ledic | Gulin, Sandra Jerkovic | Hadzavdic, Suzana Ljubojevic | Ceovic, Romana | De Francisco, Ana Montoro | De Vicente Jiménez, Talía | Luque, Amelia García | David, Natalia Rosado | Galván, José Mª Mateos | Darlenski, Razvigor | Gulin, Dario | Sikic, Jozica | Habek, Jasna Cerkez | Galic, Edvard | Specht, Philip | Staab, Doris | Mayer, Beate | Roehmel, Jobst | Solovan, Caius | Chiriac, Anca | Djurinec, Paola | Kostovic, Kresimir | Bradamante, Mirna | Almeida, Jose Pedro | Caiado, Joana | Pedro, Elisa | Da Silva, Pedro Canas | Barbosa, Manuel Pereira | Bogas, Gador | Blanca-López, Natalia | Pérez-Alzate, Diana | Doña, Inmaculada | Agúndez, José Augusto | García-Martín, Elena | Cornejo-García, José Antonio | Mayorga, Cristobalina | Torres, María José | Canto, Maria Gabriela | Blanca, Miguel | Aksakal, Sengül | Sin, Aytül Zerrin | Koç, Zeynep Peker | Günsen, Fatma Düsünür | Ardeniz, Ömür | Gökmen, Emine Nihal Mete | Gülbahar, Okan | Kokuludag, Ali | Pérez-Sánchez, Natalia | Salas, María | Salas, Maria | Gomez, Francisca | Barrionuevo, Esther | Andreu, Inmaculada | Miranda, Miguel Ángel | Didžiokaite, Gabija | Gaidej, Olesia | Kašinskaite, Simona | Garcimartin, Maria Isabel | Somoza, Maria Luisa | Bojas, Gador | Cornejo-Garcia, Jose Antonio | Perez, Francisco Javier Ruano | Miranda, Miguel Angel | Jerschow, Elina | Pelletier, Teresa | Ren, Zhen | Hudes, Golda | Sanak, Marek | Morales, Esperanza | Schuster, Victor | Spivack, Simon D | Rosenstreich, David | Erzen, Renato | Silar, Mira | Bajrovic, Nissera | Rijavec, Matija | Zidarn, Mihaela | Korosec, Peter | Castro, Eunice | Al-Ahmad, Mona | Rodriguez, Tito | Azevedo, João Pedro | Tavares, Beatriz | Regateiro, Frederico | Todo-Bom, Ana | Miranda, Pablo Andrés | De La Cruz Hoyos, Bautista | Abuzeid, Waleed | Akbar, Nadeem | Gibber, Marc | Fried, Marvin | Han, Weiguo | Keskin, Taha | Tamayev, Robert | Spivack, Simon D. | Rosenstreich, David | Jerschow, Elina | Boni, Elisa | Russello, Marina | Mauro, Marina | Neto, Marta Ferreira | Brosseron, Lise | Malheiro, Daniela | Barreira, Patrícia | Sprigg, Dustin | Trevenen, Michelle | Seet, Jason | Trubiano, Jason | Smith, William | Jeelall, Yogesh | Vale, Sandra | Loh, Richard | Mclean-Tooke, Andrew | Müller, Sabine | Amstutz, Ursula | Jörg, Lukas | Yawalkar, Nikhil | Krähenbühl, Stephan | Leblanc, Ana | Ribeiro, Laura | Vega, Arantza | Rivas, Raquel Gutierrez | Alonso, Ana | Beitia, Juan Maria | Mateo, Belén | Cárdenas, Remedios | Garcia-Dominguez, Juan Jesus | Pavlos, Rebecca | Strautins, Kaija | James, Ian | Mallal, Simon | Redwood, Alec | Aguiar, Rita | Lopes, Anabela | Neves, Ana | Do Céu Machado, Maria | Dalgiç, Ceyda Tunakan | Gökmen, Emine Nihal Mete | Bulut, Gökten | Ardeniz, Fatma Ömür | Gülbahar, Okan | Sin, Aytül Zerrin | Hsu, Shao-Hsuan | Yang, Che-Wen | Ye, Young-Min | Hur, Gyu-Young | Park, Hae-Sim | Kim, Seung-Hyun | Ali, Syed | Hollingsworth, Peter N. | Mclean-Tooke, Andrew P. C. | Chadly, Zohra | Fredj, Nadia Ben | Aouam, Karim | Romdhane, Haifa Ben | Boughattas, Naceur A. | Chaabane, Amel | Salazar, Marina Lluncor | Pola, Beatriz | Fiandor, Ana | Ramírez, Elena | Ortega, Javier Domínguez | Quirce, Santiago | Cabañas, Rosario | Baynova, Krasimira | Labella, Marina | Prados, Manuel | Ramonaite, Agne | Bajoriuniene, Ieva | Sitkauskiene, Brigita | Sakalauskas, Raimundas | Kwon, Jae-Woo | Park, Shinyoung | Silva, Diana | Leão, Leonor Carneiro | Castro, Eunice | Garcimartin, Maria | De La Torre, Maria Vazquez | Pérez, Francisco Javier Ruano | Haroun, Elisa | Diez, Gabriela Canto | Ónodi-Nagy, Katinka | Kinyó, Ágnes | Kemény, Lajos | Bata-Csörgo, Zsuzsanna | Pita, Joana Sofia | Fernandes, Rosa Anita | Moura, Ana | Sousa, Nuno | Loureiro, Carlos | Pfützner, Wolfgang | Marrouche, Nadine | Grattan, Clive | Chen, Yu-En | Chen, Chun-Bing | Hsiao, Yu-Ping | Garcimartin, Maria Isabel | Ruano, Francisco Javier
Table of contents
Oral Abstracts
O1 Functionally distinct HMGB1 isoforms correlate with physiological processes in drug-induced SJS/TEN
Daniel F. Carr, Wen-Hung Chung, Rosalind E. Jenkiins, Mas Chaponda, Gospel Nwikue, Elena M. Cornejo Castro, Daniel J. Antoine, Munir Pirmohamed
O2 Hypersensitivity reactions to beta-lactams, does the t cell recognition pattern influence the clinical picture?
Natascha Wuillemin, Dolores Dina, Klara K. Eriksson, Daniel Yerly
O3 Specific binding characteristics of HLA alleles associated with nevirapine hypersensitivity
Rebecca Pavlos, Elizabeth Mckinnin, David Ostrov, Bjoern Peters, Soren Buus, David Koelle, Abha Chopra, Craig Rive, Alec Redwood, Susana Restrepo, Austin Bracey, Jing Yuan, Silvana Gaudieri, Mary Carrington, David Haas, Simon Mallal, Elizabeth Phillips
O4 Do we need to measure total ige for the interpretation of analytical results of ImmunoCAP dnd 3gAllergy specific IgE?
Douwe De Boer, Paul Menheere, Chris Nieuwhof, Judith Bons
O5 Neutrophil activation in systemic anaphylaxis: results from the multicentric NASA study
Friederike Jonsson, Luc De Chaisemartin, Vanessa Granger, Caitlin Gillis, Aurelie Gouel, Catherine Neukirch, Fadia Dib, Pascale Roland Nicaise, Dan Longrois, Florence Tubach, Sylvie Martin, Pierre Bruhns, NASA Study Group
O6 Purpuric drug eruptions due to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for non-small-cell lung cancer (NSCLC): a clinic-pathological study of 32 cases
Kai-Lung Chen, Shu-Ling Liao, Yi-Shuan Sheen, Yung-Tsu Cho, Che-Wen Yang, Jau-Yu Liau, Chia-Yu Chu
Poster presentations: Poster Walk 1—Anaphylaxis (P01–P09)
P1 Anaphylactic reactions during anaesthesia and the perioperative period
Rita Aguiar, Anabela Lopes, Natália Fernandes, Leonor Viegas, M. A. Pereira-Barbosa
P2 Anaphylaxis to chlorhexidine: is there a cross-reactivity to alexidine?
Antonia Bünter, Nisha Gupta, Tatjana Pecaric Petkovic, Nicole Wirth, Werner J. Pichler, Oliver Hausmann
P3 Cefotaxime-induced severe anaphylaxis in a neonate
Mehtap Yazicioglu, Pinar G. Ozdemir, Gokce Ciplak, Ozkan Kaya
P4 Clinical features and diagnosis of anaphylaxis resulting from exposure to chlorhexidine
Peter John Cooke
P5 Drug-induced anaphylaxis: five-year single-center survey
Inês Mota, Ângela Gaspar, Filipe Benito-Garcia, Marta Chambel, Mário Morais-Almeida
P6 Intraoperative severe anaphylactic reaction due to patent blue v dye
Luis Marques, Eva Alcoceba, Silvia Lara
P7 Kounis syndrome in the setting of anaphylaxis to diclofenac
Leonor Carneiro-Leão, Carmen Botelho, Eunice Dias-Castro, Josefina Cernadas
P8 Perioperative anaphylaxis audit: Royal Melbourne Hospital
Katherine Nicholls, William Lay, Olivia Smith, Christine Collins, Gary Unglik, Kymble Spriggs, Priscilla Auyeung, Jeremy McComish, Jo A. Douglass
P9 Recurrent peri-operative anaphylaxis: a perfect storm
Jonny G. Peter, Paul Potter
Poster Walk 2: DH regions and patient groups (P10–P19)
P10 A rare presentation of amoxicillin allergy in a young child
Fabrícia Carolino, Eunice Dias De Castro, Josefina R. Cernadas
P11 Adverse drug reactions in children: antibiotics or virus?
Ana Sofia Moreira, Carmo Abreu, Eva Gomes
P12 Allergic reactions in invasive medical procedures
Bárbara Kong Cardoso, Elza Tomaz, Sara Correia, Filipe Inácio
P13 Antibiotic allergy in children: room for improvement
Annabelle Arnold, Natasha Bear, Kristina Rueter, Grace Gong, Michael O’Sullivan, Saravanan Muthusamy, Valerie Noble, Michaela Lucas
P14 Drug hypersensitivity reactions in children and results of diagnostic evaluation
Neringa Buterleviciute, Odilija Rudzeviciene
P15 Nonimmediate cutaneous drug reactions in children: are skin tests required?
Ana Sofia Moreira, Carmo Abreu, Eva Gomes
P16 Pediatric patients with a history of penicillin allergy and a positive penicillin skin test may not be at an increased risk for multiple drug allergies
Sara May, Thanai Pongdee, Miguel Park
P17 Proved hypersensitivity to drugs according data of Vilnius University Hospital Santariskiu Klinikos
Linas Griguola, Arturas Vinikovas, Simona Kašinskaite, Violeta Kvedariene
P18 Self-reported prevalence of drug hypersensitivity reactions among students in Celal Bayar University, Turkey
Ayse Aktas, Suheyla Rahman, Huseyin Elbi, Beyhan Cengiz Ozyurt
P19 Severe drug hypersensitivity reactions in pediatric age
Ozlem Cavkaytar, Betul Karaatmaca, Pinar Gur Cetinkaya, Saliha Esenboga, Umit M. Sahiner, Bulent E. Sekerel, Ozge Soyer
Poster Walk 3: Desensitisation (P20–P28)
P20 A protocol for desensitisation to valaciclovir
Celia Zubrinich, Bianca Tong, Mittal Patel, Michelle Giles, Robyn O’Hehir, Robert Puy
P21 A rare case of desensitization to modafinil
Josefina Cernadas, Luís Amaral, Fabrícia Carolino
P22 A sixteen-day desensitization protocol in delayed type hypersensitivity reactions to oral drugs
Semra Demir, Asli Gelincik, Muge Olgac, Raif Caskun, Derya Unal, Bahauddin Colakoglu, Suna Buyukozturk
P23 Desensitization to intravenous etoposide using a 12 and a 13-step protocol. Two cases report
Olga Vega Matute, Amalia Bernad, Gabriel Gastaminza, Roselle Madamba, Carlos Lacasa, M. J. Goikoetxea, Carmen D’Amelio, Jose Rifón, Nicolas Martínez, Marta Ferrer
P24 Drug desensitisation in oncology: the experience of an immunoallergology department for 5 years
Carmelita Ribeiro, Emília Faria, Cristina Frutuoso, Anabela Barros, Rosário Lebre, Alice Pego, Ana Todo Bom
P25 Filgrastim anaphylaxis: a successful desensitization protocol
Luis Amaral, Josefina Cernadas
P26 Galsulfase hypersensitivity and desensitization of a mucopolysaccharidosis VI patient
Luis Felipe Ensina, Carolina Aranda, Ines Camelo Nunes, Ana Maria Martins, Dirceu Solé
P27 Rapid drug desensitization with biologicals: one-center experience with four biologicals
Sevim Bavbek, Resat Kendirlinan, Pamir Çerçi, Seda Tutluer, Sadan Soyyigit, Zeynep Çelebi Sözener, Ömür Aydin, Reyhan Gümüsburun
P28 Successful desensitization to a high dose of methotrexate in a delayed type hypersensitivity reaction
Josefina Cernadas, Leonor Carneiro-Leão, Fabrícia Carolino, Marta Almeida
Poster Walk 4: SJS (P29–P38)
P29 Assessment of impact of infection on drug-induced severe cutaneous adverse reactions and rhabdomyolysis using the Japanese adverse drug event report database
Kimie Sai, Takuya Imatoh, Ryosuke Nakamura, Chisato Fukazawa, Yasushi Hinomura, Yoshiro Saito
P30 Characterization of erythema multiforme and severe cutaneous adverse reactions hospitalizations
Bernardo Sousa-Pinto, Cláudia Correia, Lídia Gomes, Sara Gil-Mata, Luís Araújo, Luís Delgado
P31 Effects of infection on incidence/severity of SJS/TEN and myopathy in Japanese cases analyzed by voluntary case reports
Ryosuke Nakamura, Kimie Sai, Takuya Imatoh, Yoshimi Okamoto-Uchida, Koji Kajinami, Kayoko Matsunaga, Michiko Aihara, Yoshiro Saito
P32 Efficacy of tumor necrosis factor—a antagonists in Stevens–Johnson syndrome and toxic epidermal necrolysis: a randomized controlled trial and immunosuppressive effects evaluation
Chuang-Wei Wang, Shih-Chi Su, Shuen-Iu Hung, Hsin-Chun Ho, Chih-Hsun Yang, Wen-Hung Chung
P33 Evolution of drug causality in Stevens–Johnson syndrome and toxic epidermal necrolysis in Europe: analysis of 10 years RegiSCAR-Study
Maren Paulmann, Ariane Dunant, Maja Mockenhaupt, Peggy Sekula, Martin Schumacher, Sylvia Kardaun, Luigi Naldi, Teresa Bellón, Daniel Creamer, Cynthia Haddad, Bruno Sassolas, Bénédicte Lebrun-Vignes, Laurence Valeyrie-Allanore, Jean-Claude Roujeau
P34 Long-term sequelae in patients with Stevens–Johnson syndrome and toxic epidermal necrolysis: a 5-year analysis
Maren Paulmann, Carmen Kremmler, Peggy Sekula, Laurence Valeyrie-Allanore, Luigi Naldi, Sylvia Kardaun, Maja Mockenhaupt
P35 Major emotional complications and decreased health related quality of life among survivors of Stevens–Johnson syndrome and toxic epidermal necrolysis
Roni P. Dodiuk-Gad, Cristina Olteanu, Anthony Feinstein, Rena Hashimoto, Raed Alhusayen, Sonia Whyte-Croasdaile, Yaron Finkelstein, Marjorie Burnett, Shachar Sade, Robert Cartotto, Marc Jeschke, Neil H. Shear
P36 Retrospective analysis of Stevens–Johnson syndrome and toxic epidermal necrolysis in Japanese patients: treatment and outcome
Naoko Takamura, Yumiko Yamane, Setsuko Matsukura, Kazuko Nakamura, Yuko Watanabe, Yukie Yamaguchi, Takeshi Kambara, Zenro Ikezawa, Michiko Aihara
P37 Severe physical complications among survivors of Stevens–Johnson syndrome and toxic epidermal necrolysis
Roni P. Dodiuk-Gad, Cristina Olteanu, Rena Hashimoto, Hall Chew, Raed Alhusayen, Sonia Whyte-Croasdaile, Yaron Finkelstein, Marjorie Burnett, Shachar Sade, Robert Cartotto, Marc Jeschke, Neil H. Shear
P38 Stevens–Johnson syndrome/toxic epidermal necrolysis combined with haemophagocytic lymphohistiocytosis: a case report
Brittany Knezevic, Una Nic Ionmhain, Allison Barraclough, Michaela Lucas, Matthew Anstey
Poster Walk 5: Other organs/unexpected immune reactions (P39–P47)
P39 A case report of patient with anti-tuberculosis drug-related severe liver failure
Toru Usui, Xiaoli Meng, John Farrell, Paul Whitaker, John Watson, Neil French, Kevin Park, Dean Naisbitt
P40 Acute interstitial nephritis induced by ibuprofen
Ana Castro Neves, Susana Cadinha, Ana Moreira, J. P. Moreira Da Silva
P41 Cetuximab induced acneiform rash—two case reports
Daniela Ledic Drvar, Sandra Jerkovic Gulin, Suzana Ljubojevic Hadzavdic, Romana Ceovic
P42 Enteropathy associated with losartan
Ana Montoro De Francisco, Talía De Vicente Jiménez, Amelia García Luque, Natalia Rosado David, José Mª Mateos Galván
P43 Granuloma annulare after therapy with canakinumab
Razvigor Darlenski
P44 Hypersensitivity eosinophilic myocarditis or acute coronary syndrome? Case report
Dario Gulin, Jozica Sikic, Jasna Cerkez Habek, Sandra Jerkovic Gulin, Edvard Galic
P45 Piperacillin-induced immune haemolytic anaemia: a severe and frequent complication of antibiotic treatment in patients with cystic fibrosis
Philip Specht, Doris Staab, Beate Mayer, Jobst Roehmel
P46 Progesterone triggered pemphigus foliaceus: case report
Sandra Jerkovic Gulin, Caius Solovan, Anca Chiriac
P47 Ramipril: triggered generalized pustular psoriasis
Paola Djurinec, Kresimir Kostovic, Mirna Bradamante, Sandra Jerkovic Gulin, Romana Ceovic
Poster Walk 6: NSAIDs (P48–P56)
P48 Aspirin desensitization in cardiovascular disease—Portuguese experience
Jose Pedro Almeida, Joana Caiado, Elisa Pedro, Pedro Canas Da Silva, Manuel Pereira Barbosa
P49 Asthma and/or rhinitis to NSAIDs with good tolerance to ASA
Gador Bogas, Natalia Blanca-López, Diana Pérez-Alzate, Inmaculada Doña, José Augusto Agúndez, Elena García-Martín, José Antonio Cornejo-García, Cristobalina Mayorga, María José Torres, Gabriela Canto, Miguel Blanca
P50 Clinical characteristics of 196 patients with non-steroidal anti-inflammatory drug (NSAIDs) hypersensitivity
Sengül Aksakal, Aytül Zerrin Sin, Zeynep Peker Koç, Fatma Düsünür Günsen, Ömür Ardeniz, Emine Nihal Mete Gökmen, Okan Gülbahar, Ali Kokuludag
P51 Development of immediate hypersensitivity to several NSAIDs maintaining good tolerance to ASA
Natalia Pérez-Sánchez, Natalia Blanca-López, Diana Pérez-Alzate, Gador Bogas, Inmaculada Doña, María Salas, María José Torres, Miguel Blanca, Gabriela Canto
P52 Diagnosis of hypersensitivity reactions to paracetamol in a large series of cases
Inmaculada Doña, Maria Salas, Francisca Gomez, Natalia Blanca-Lopez, Diana Perez-Alzate, Gador Bogas, Esther Barrionuevo, Maria Jose Torres, Inmaculada Andreu, Miguel Ángel Miranda, Gabriela Canto, Miguel Blanca
P53 Hypersensitivity to paracetamol according to the new classification of hypersensitivity to NSAIDs
Gabija Didžiokaite, Olesia Gaidej, Simona Kašinskaite, Violeta Kvedariene
P54 Ibuprofen and other aryl propionic derivates can induce immediate selective hypersensitivity responses
Diana Perez-Alzate, Natalia Blanca-López, Maria Isabel Garcimartin, Inmaculada Doña, Maria Luisa Somoza, Cristobalina Mayorga, Maria Jose Torres, Gador Bojas, Jose Antonio Cornejo-Garcia, Maria Gabriela Canto, Miguel Blanca
P55 Subjects developing immediate responses to several NSAIDs can be selective with good tolerance to ASA
Natalia Blanca-Lopez, Diana Pérez-Alzate, Francisco Javier Ruano Perez, Inmaculada Doña, Maria Luisa Somoza, Inmaculada Andreu, Miguel Angel Miranda, Cristobalina Mayorga, Maria Jose Torres, Jose Antonio Cornejo-Garcia, Miguel Blanca, Maria Gabriela Canto
P56 Utility of low-dose oral aspirin challenges for diagnosis of aspirin exacerbated respiratory disease
Elina Jerschow, Teresa Pelletier, Zhen Ren, Golda Hudes, Marek Sanak, Esperanza Morales, Victor Schuster, Simon D. Spivack, David Rosenstreich
Poster Walk 7: NSAID 2 (P57–P65)
P57 Alternate regulation of cyclooxygenase-2 (COX-2) MRNA expression may predispose patients to aspirin-induced exacerbations
Renato Erzen, Mira Silar, Nissera Bajrovic, Matija Rijavec, Mihaela Zidarn, Peter Korosec
P58 Anaphylaxis to diclofenac: what about the underlying mechanism?
Leonor Carneiro-Leão, Fabrícia Carolino, Luís Amaral, Carmen Botelho, Eunice Dias-Castro, Josefina Cernadas
P59 COX-2 inhibitors: are they always a safe alternative in hypersensitivity to nonsteroidal anti-inflammatory drugs?
Luis Amaral, Fabricia Carolino, Eunice Castro, Josefina Cernadas
P60 Management of patients with history of NSAIDs reactions prior to coronary angioplasty
Mona Al-Ahmad, Tito Rodriguez
P61 Oral drug challenge with non-steroidal anti-inflammatory drug under spirometric control: clinical series of 110 patients
João Pedro Azevedo, Emília Faria, Beatriz Tavares, Frederico Regateiro, Ana Todo-Bom
P62 Prevalence and incidence of analgesic hypersensitivity reactions in Colombia
Pablo Andrés Miranda, Bautista De La Cruz Hoyos
P63 Recent endoscopic sinus surgery lessens reactions during aspirin challenge in patients with aspirin exacerbated respiratory disease
Teresa Pelletier, Waleed Abuzeid, Nadeem Akbar, Marc Gibber, Marvin Fried, Weiguo Han, Taha Keskin, Robert Tamayev, Golda Hudes, Simon D. Spivack, David Rosenstreich, Elina Jerschow
P64 Safe use of imidazole salycilate in a case of multiple NSAIDs induced urticaria-angioedema
Elisa Boni, Marina Russello, Marina Mauro
P65 Selective hypersensitivity reactions to ibuprofen—seven years experience
Marta Ferreira Neto
Poster Walk 8: Epidemiological methods (P66–P72)
P66 Allopurinol hypersensitivity: a 7-year review
Lise Brosseron, Daniela Malheiro, Susana Cadinha, Patrícia Barreira, J. P. Moreira Da Silva
P67 Antibiotic allergy labelling is associated with increased hospital readmission rates in Australia
Brittany Knezevic, Dustin Sprigg, Michelle Trevenen, Jason Seet, Jason Trubiano, William Smith, Yogesh Jeelall, Sandra Vale, Richard Loh, Andrew Mclean-Tooke, Michaela Lucas
P68 Experts’ opinions on severe cutaneous adverse drug reactions-report of a survey from the 9th international congress on cutaneous adverse drug reactions 2015
Roni P. Dodiuk-Gad, Cristina Olteanu, Wen-Hung Chung, Neil H. Shear
P69 HLA-A*31-positive AGEP with carbamazepine use and other severe cutaneous adverse drug reactions (SCARs) detected by electronic medical records screening
Sabine Müller, Ursula Amstutz, Lukas Jörg, Nikhil Yawalkar, Stephan Krähenbühl
P70 Patients with suspected drug allergy: a specific psychological profile?
Eunice Dias-Castro, Ana Leblanc, Laura Ribeiro, Josefina R. Cernadas
P71 Use of an electronic device and a computerized mathematic algorithm to detect the allergic drug reactions through the analysis of heart rate variability
Arantza Vega, Raquel Gutierrez Rivas, Ana Alonso, Juan Maria Beitia, Belén Mateo, Remedios Cárdenas, Juan Jesus Garcia-Dominguez
P72 Variation in ERAP influences risk for HLA-B*57:01 positive abacavir hypersensitivity
Rebecca Pavlos, Kaija Strautins, Ian James, Simon Mallal, Alec Redwood, Elizabeth Phillips
Poster Walk 9: DRESS/AGEP (P73–P81)
P73 A clinical case of DRESS syndrome in a child after administration of amoxicillin-clavulanic acid
Rita Aguiar, Anabela Lopes, Ana Neves, Maria Do Céu Machado, M. A. Pereira-Barbosa
P74 Acute generalized exanthematous pustulosis (AGEP) induced by mesalazine, reliable and oftenly used drug to treat inflammatory bowel disease
Ceyda Tunakan Dalgiç, Emine Nihal Mete Gökmen, Fatma Düsünür Günsen, Gökten Bulut, Fatma Ömür Ardeniz, Okan Gülbahar, Ali Kokuludag, Aytül Zerrin Sin
P75 Changes of blood plasmacytoid dendritic cells, myeloid dendritic cells, and basophils during the acute stage of drug reaction with eosinophilia and systemic symptoms (DRESS) and other drug eruptions
Shao-Hsuan Hsu, Yung-Tsu Cho, Che-Wen Yang, Kai-Lung Chen, Chia-Yu Chu
P76 Characterization of isoniazid/rifampicin-specific t-cell responses in patients with DRESS syndrome
Young-Min Ye, Gyu-Young Hur, Hae-Sim Park, Seung-Hyun Kim
P77 DRESS syndrome secondary to sulfasalazine with delayed TEN: a case presentation
Syed Ali, Michaela Lucas, Peter N. Hollingsworth, Andrew P. C. Mclean-Tooke
P78 Drug rash with eosinophilia and systemic symptoms (DRESS) features according to the culprit drug
Zohra Chadly, Nadia Ben Fredj, Karim Aouam, Haifa Ben Romdhane, Naceur A. Boughattas, Amel Chaabane
P79 Drug reaction with eosinophilia and systemic symptoms induced by allopurinol: not always easy to diagnose
Marina Lluncor Salazar, Beatriz Pola, Ana Fiandor, Teresa Bellón, Elena Ramírez, Javier Domínguez Ortega, Santiago Quirce, Rosario Cabañas
P80 Drug reaction with eosinophilia and systemic symptoms syndrome induced by two drugs simultaneously: a case report
Krasimira Baynova, Marina Labella, Manuel Prados
P81 The drug reaction with eosinophilia and systemic symptoms (DRESS) induced by the second-line antituberculosis drugs and Epstein–Barr virus infection
Agne Ramonaite, Ieva Bajoriuniene, Brigita Sitkauskiene, Raimundas Sakalauskas
Poster Walk 10: Miscellaneous drug hypersensitivity (P82–P91)
P82 A case of cycloserine-induced lichenoid drug eruption confirmed with a lymphocatye transformation test
Jae-Woo Kwon, Shinyoung Park
P83 Allergic reaction to topical eye drops: 5 years’ retrospective study in a drug allergy unit
Diana Silva, Leonor Carneiro Leão, Fabricia Carolino, Eunice Castro, Josefina Cernadas
P84 Allergy to heparins
Diana Perez-Alzate, Natalia Blanca-López, Maria Luisa Somoza Alvarez, Maria Garcimartin, Maria Vazquez De La Torre, Francisco Javier Ruano Pérez, Elisa Haroun, Gabriela Canto Diez
P85 Allopurinol-induced adverse drug reactions
Katinka Ónodi-Nagy, Ágnes Kinyó, Lajos Kemény, Zsuzsanna Bata-Csörgo
P86 Analysis of a population with immediate hypersensitivity to corticosteroids: an 11 year review
Joana Sofia Pita, Emília Faria, Rosa Anita Fernandes, Ana Moura, Nuno Sousa, Carmelita Ribeiro, Carlos Loureiro, Ana Todo Bom
P87 Anaphylaxis against mivacurium in a 12-months old boy at first-time exposure
Wolfgang Pfützner
P88 Antihistamine-exacerbated chronic spontaneous urticaria: a paradox?
Nadine Marrouche, Clive Grattan
P89 Anti-osteoporotic agents-induced cutaneous adverse drug reactions in Asians
Yu-En Chen, Chun-Bing Chen, Wen-Hung Chung, Yu-Ping Hsiao, Chia-Yu Chu
P90 Diagnosis of allergic reactions to eye drops
Maria Vazquez De La Torre, Natalia Blanca-Lopez, Diana Perez-Alzate, Maria Isabel Garcimartin, Francisco Javier Ruano, Maria Luisa Somoza, Elisa Haroun, Gabriela Canto
P91 Diagnostic approach in suspected hypersensitivity reactions to corticosteroids
Fabrícia Carolino, Eunice Dias De Castro, Josefina R. Cernadas
PMCID: PMC5009634
25.  Comparison of Four Comamonas Catabolic Plasmids Reveals the Evolution of pBHB To Catabolize Haloaromatics 
Comamonas plasmids play important roles in shaping the phenotypes of their hosts and the adaptation of these hosts to changing environments, and understanding the evolutionary strategy of these plasmids is thus of great concern. In this study, the sequence of the 119-kb 3,5-dibromo-4-hydroxybenzonitrile-catabolizing plasmid pBHB from Comamonas sp. strain 7D-2 was studied and compared with those of three other Comamonas haloaromatic catabolic plasmids. Incompatibility group determination based on a phylogenetic analysis of 24 backbone gene proteins, as well as TrfA, revealed that these four plasmids all belong to the IncP-1β subgroup. Comparison of the four plasmids revealed a conserved backbone region and diverse genetic-load regions. The four plasmids share a core genome consisting of 40 genes (>50% similarities) and contain 12 to 50 unique genes each, most of which are xenobiotic-catabolic genes. Two functional reductive dehalogenase gene clusters are specifically located on pBHB, showing distinctive evolution of pBHB for haloaromatics. The higher catabolic ability of the bhbA2B2 cluster than the bhbAB cluster may be due to the transcription levels and the character of the dehalogenase gene itself rather than that of its extracytoplasmic binding receptor gene. The plasmid pBHB is riddled with transposons and insertion sequence (IS) elements, and ISs play important roles in the evolution of pBHB. The analysis of the origin of the bhb genes on pBHB suggested that these accessory genes evolved independently. Our work provides insights into the evolutionary strategies of Comamonas plasmids, especially into the adaptation mechanism employed by pBHB for haloaromatics.
PMCID: PMC4771318  PMID: 26682859

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